The Humanities Center at Johns Hopkins University emerged from a constellation of factors in the mid-twentieth century. A condensation of the "humanities group" at the university (made up of the various humanities departments), the Center provided a means to concentrate and strengthen the humanities departments at Hopkins, which were already feeling the strain of the increasing importance of the sciences relative to the humanities. The Center also offered a focal point in the university and the US for engagement with structuralist thought, which was just then at its most influential in the European and (increasingly) American academies. Finally, the directorship of the Center constituted an appealing position to offer to the renowned Dante scholar, Charles Singleton, whom the university was eager to regain (Singleton had served as a professor in the university's Italian department for some years before a brief departure to Harvard). Of primary importance in the conception of the Humanities Center was the role it would play within the university. For some time, the humanities group at Hopkins had been organizing a yearly seminar series, in which members from the group's many departments took part. The positive results of such collaborative sessions led to the desire to make it official: the Humanities Center would serve formally to bring together the various humanities departments. All members of these departments were ipso facto members of the Humanities Center, and the Center's original governing body consisted of the director of the Center, the chairman of the humanities group, and 3 councilors elected from among the humanities departments. Furthermore, while the Center had a few fellows and grad students of its own, the Center's seminars and lectures were attended in large part by faculty and students from other departments, a condition which continues to characterize the Center. Discussion in the Humanities Center serves as a site of interdepartmental conversation and criticism, adding to the strengths of the individual humanities departments by constituting a common space of intellectual exchange.

The germ of the Humanities Center consisted in discussion and planning between members of the university's humanities departments and the university administration (especially then-president Milton S. Eisenhower, who enthusiastically supported the proposed Center) in the early 1960s; the Center saw its first full academic year in 1966-67. This period corresponded to a moment of intense excitement about structuralist thought. The Center's founders were very much in touch with this primarily European current of thought, and sought to establish a focal site for structuralism in the US on the model of the "sixième section" of the École Pratique des Hautes Études in Paris (which, in 1975, became independent to form the École des Hautes Études en Sciences Sociales) or the Institut für Soziologie at the University of Frankfurt under the direction of Theodor Adorno. The Humanities Center fulfilled this role with éclat: the conference held in the fall of its inaugural year, "The Languages of Criticism and the Sciences of Man: The Structural Controversy" brought the champions of European thought together in the US, and continues to be cited as both the substantial introduction of structuralist thought into the American academy, and an important moment of transition between structuralism and post-structuralism (particularly Jacques Derrida's paper delivered at the conference, "Structure, Sign, and Play in the Discourse of the Human Sciences"). Furthermore, Derrida was a regular guest in the early years of the Center, as was Paul de Man, who held a regular appointment there for several years.

This early model of exchange and innovation, at the institutional, national, and international levels, has been sustained. From its beginning, the Humanities Center has provided the university with a robust program of visiting scholars, professors, and lecturers. The Center's connections with centers of thought elsewhere, such as Paris, Hamburg, Berlin, Strasbourg, and, more recently, Amsterdam, not only facilitates intellectual exchange and affords an opportunity to bring international scholars to the Hopkins campus, but also affords faculty and students crucial opportunities for research abroad. Within Hopkins, the Center has served as a sort of testing ground for various university ventures; for example, courses in film studies, which has since become an independent program at Hopkins, were first pioneered in the Humanities Center, with faculty borrowed from other institutions. The Center's flexibility in terms of content has enabled it to make a unique contribution to the university's undergraduate course offerings: the Center consistently offers both "core" courses (e.g. great books) and some of the most innovative and original thematic small-group seminars available to undergraduates, including courses on genocide and trauma, Russian literature, Jewish philosophy, modernist art, the city of Baltimore, 20th-century German political thought, and philosophies of time.